Radiopharmaceutical MOFs for medical imaging

Abstract

The present invention relates to MOFs for use in imaging and as radiolabeled tracers. More specifically, the present invention provides particles comprising MOFs, optionally at least one targeting moiety, and at least one short-lived radionuclide; compositions comprising the particles; the particles or compositions for use as imaging agents; the particles or compositions for use in methods for diagnosing proliferative diseases; the particles or compositions for use in methods for diagnosing chronic inflammatory diseases; and kits comprising particles comprising MOFs, optionally a targeting moiety, and a short-lived radionuclide cation.

Description

[Technical Field]

[0001] The present invention relates to MOFs for use in imaging and as radiolabeled tracers. More specifically, the present invention provides particles comprising a MOF and at least one short-lived radionuclide; particles comprising a MOF, at least one targeting moiety, and at least one short-lived radionuclide; compositions comprising the particles; the particles or compositions for use as imaging agents; the particles or compositions for use in methods for diagnosing proliferative diseases; and kits comprising particles comprising a MOF and optionally a targeting moiety, and a short-lived radionuclide cation. [Background technology]

[0002] Cancer is a widespread group of diseases that directly or indirectly affect millions of people. The WHO estimates that 19.3 million new cases of cancer will occur in 2020, and 50.6 million people will have a five-year life expectancy. Despite decades of improvements in treatment, the American Cancer Society predicts that by 2040, the number of new cancer cases will increase to 27.5 million per year, and the number of cancer-related deaths will increase to 16.2 million per year. Common methods of cancer treatment include surgery, chemotherapy, and external beam radiation therapy. However, there is a significant unmet medical need for new and more effective cancer treatment options.

[0003] One promising therapeutic approach with high specificity and efficacy is theranostic therapy, which combines diagnostic and cancer-killing radioisotopes (e.g., gamma and alpha radiation). Theranostic therapy uses the same delivery compound, but only changes the radioisotope. This allows for assessment of the biodistribution of the diagnostic compound before administering cancer-killing radiopharmaceuticals, such as radioimmunotherapy (RIT) or targeted alpha therapy (TAT). RIT agents are based on a tissue targeting moiety attached to a carrier capable of binding and retaining the radioisotope. This tissue targeting moiety, often an antibody, is used to deliver the radioisotope to the vicinity of unwanted cells, such as cancer cells, resulting in the localized delivery of high-energy, cytotoxic radiation, killing the unwanted cells while sparing healthy surrounding tissue. Such specific cell death is essential for the treatment of cancerous diseases, such as sarcomas and carcinomas, as well as hyperplastic and neoplastic diseases and chronic inflammatory diseases. Furthermore, systemic treatment with RIT is highly effective in patients with metastatic tumors that are otherwise difficult to reach without adverse side effects.

[0004] Successful delivery of radiation to unwanted cells relies on stable radioisotope-carrier interactions to prevent unintended side effects due to leakage of radioisotopes, particularly alpha-emitting radium isotopes, including radium-223 and radium-224. Novel therapeutic radiopharmaceuticals are being developed. One type of novel radioisotope-carrier under investigation is crystalline porous coordination polymers (PCPs), also known as metal-organic frameworks (MOFs), which are constructed by substituting inorganic and organic monomers for pores in a three-dimensional network. The interior pores of MOF particles can possess strong binding sites to which cationic radioisotopes can be strongly attached, for example, by chelation. These porous coordination polymer particles based on MOFs differ from, for example, coordination polymer nanoparticles (CPNs) associated with non-porous organic salts, which are in the form of dense particles, and from ultrasmall PEGylated polyvinylpyrrolidone (PVP) particles containing encapsulated iron-gallic acid coordination complexes as disclosed by Jin, Q et al., Nanoscale, 2017, vol. 9, no. 34, pp. 12609-12617.

[0005] RIT drugs are antibody-drug conjugates that use a targeting unit (antibody) to deliver a radioisotope to the tumor via the bloodstream, where the emitted radiation eradicates the cancer cells. Controlled radionuclide administration is a new form of targeted treatment for metastatic cancer. That is, radionuclides that emit high-energy particles upon decay allow for precise microradiation of small cell clusters without harming neighboring healthy cells. Unfortunately, however, not all patients and cancer types respond to such treatment due to a lack of colocalization between the drug and the cancer cells.

[0006] Medical imaging is commonly used to identify and monitor disease. Functional assessment of metabolism can also be achieved by using radionuclides with imaging modalities such as scintigraphy or positron emission tomography (PET). Radiopharmaceutical imaging agents are administered to patients and monitored by specific imaging devices, such as gamma cameras. These systems can include SPECT, PET, PET / MRI, and PET / CT imaging. Radiopharmaceuticals used for diagnostic purposes are short-lived radioactive tracers that emit gamma rays or positrons and are used to generate two-dimensional images, or alternatively, three-dimensional images through tomographic applications.

[0007] However, it remains difficult to predict how a patient and their indication will respond to planned treatment with radiopharmaceuticals.

[0008] Therefore, there is a need for improved radiotracers, imaging agents and methods for selecting patients who are likely to respond to treatment with radiopharmaceuticals, particularly those in which the radioisotope is contained in MOF particles. Summary of the Invention

[0009] The present inventors have discovered that certain metal-organic framework (MOF) structures containing specific free functional groups can adsorb and act as stable carriers of selected radionuclides in clinically relevant environments. Furthermore, these MOFs can be linked to targeting moieties in particle form, enabling targeted delivery of the particles and, therefore, the radionuclides in vivo. These particles containing short-lived radionuclides, or containing both targeting moieties and short-lived radionuclides, therefore represent promising drug candidates. The radiotracers of the present invention, which contain MOFs as carriers of short-lived radionuclides, can be used in medical imaging diagnostics, such as for pre-screening patients diagnosed with proliferative diseases, to predict response to treatment with alpha-emitting radionuclides, for example.

[0010] In one aspect, the present invention relates to a particle, said particle comprising: a repeating three-dimensional network of inorganic and organic monomers that forms pores; and at least one free functional group extending into the pore, the free functional group being selected from the group including carboxylic acid, carboxylate, hydroxyl, sulfonic acid, sulfonate, sulfhydryl, primary amine, secondary amine, and combinations thereof; MOFs containing; at least one short-lived radionuclide; Including, wherein said at least one radionuclide is located in at least one of the pores.

[0011] The present invention also relates to a targeted particle, said particle comprising: a repeating three-dimensional network of inorganic and organic monomers that forms pores; and at least one free functional group extending into the pore, the free functional group being selected from the group including carboxylic acid, carboxylate, hydroxyl, sulfonic acid, sulfonate, sulfhydryl, primary amine, secondary amine, and combinations thereof; MOFs containing; at least one targeting moiety linked to the particle on an exterior surface of the particle; and at least one short-lived radionuclide; Including, wherein said at least one radionuclide is located in at least one of the pores.

[0012] In a second aspect, the present invention relates to a kit comprising, in a first container: a repeating three-dimensional network of inorganic and organic monomers that forms pores; and at least one free functional group extending into the pore, the free functional group being selected from the group including carboxylic acid, carboxylate, hydroxyl, sulfonic acid, sulfonate, sulfhydryl, primary amine, secondary amine, and combinations thereof; MOF containing including particles comprising; In the second container, short-lived radionuclides Includes:

[0013] In a third aspect, the present invention relates to a contrast agent composition as further disclosed, said composition comprising at least one particle as defined above together with at least one pharmaceutically acceptable carrier, diluent, and / or excipient.

[0014] In a fourth aspect, the present invention relates to said particle or said composition, as further disclosed herein, for use as an imaging agent.

[0015] In a fifth aspect, the present invention relates to said particle or said composition for use in a method for the diagnosis of a proliferative disease, as further disclosed herein. [Brief explanation of the drawings]

[0016] [Figure 1] FIG. 1 is a schematic diagram illustrating one embodiment of the present invention. [Figure 2] Figure 2 is a schematic diagram of a network structure with an fcu topology. [Figure 3] FIG. 3 is a diagram showing the pore of fcuMOF. [Figure 4] FIG. 4 shows examples of coordination sites at the corners of a tetrahedral cage. [Figure 5] FIG. 5 shows examples of coordination sites at the corners of an octahedral pore. [Figure 6] FIG. 6 shows examples of coordination sites at the corners of an octahedral pore. [Figure 7]FIG. 7 shows examples of coordination sites at the corners of an octahedral cage. [Figure 8] FIG. 8 shows an example of a pore with multiple free functional groups extending into the pore. [Figure 9] FIG. 9 shows the MOF UiO-66. [Figure 10] FIG. 10 shows the MOF MIL-53. [Figure 11] FIG. 11 shows a MOF with a zeolitic imidazolate framework and the so-called sod topology. [Figure 12] Figure 12 shows the BCA assay of antibody (IgG) conjugated UIO-66(COOH)2. See Example 1. [Figure 13] Figure 13 shows that anti-CD37 conjugated MOF (NP1) binds to CD37-positive cells (Duadi cells). See Example 4. [Figure 14] Figure 14 shows that anti-EpCAM or anti-HER-tagged UIO-66(COOH)2 binds to colon cancer cells (HTC116 and HT29) that express both antigens. See Example 5. [Figure 15] Figure 15 shows that anti-HER2 conjugate UIO-66(COOH)2 binds to HER2-positive cancer cells (JIMT1 cells). See Example 6. [Figure 16A] Figure 16A shows in vitro cell viability of HT29 cells after 24 and 48 hours of exposure to UIO-66(COOH)2. See Example 10. [Figure 16B] Figure 16B shows in vitro cell viability of HCT116 after 24 and 48 hours of exposure to UIO-66(COOH)2. See Example 10. [Figure 17] Figure 17 shows overlaid sections of PET / CT scans of a mouse after a 0.6 MBq dose of 68Ga-labeled NPs. Images were acquired 10-30 minutes after injection. See Example 8. DETAILED DESCRIPTION OF THE INVENTION

[0017] Unless otherwise defined, all terms, notations, and other scientific or technical terms used herein are intended to have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs. In some cases, terms having a commonly understood meaning are defined herein for clarity and / or ready reference, and the inclusion of such definitions herein should not necessarily be construed as representing a substantial departure from what is commonly understood in the art.

[0018] Metal-organic frameworks (MOFs), also known as multiporous coordination polymers (PCPs), are solid compounds, usually in powder form, belonging to the coordination polymer class. Chemically, MOFs comprise a repeating network of polytopic inorganic monomers, in the form of metal ions or clusters, and organic monomers, also called bridging ligands or linkers. The inorganic and organic monomers are linked by coordinate covalent or ionic bonds between Lewis acidic metal cations and Lewis basic organic functional groups (e.g., carboxylates, amines, imines, etc.). The structure of a MOF can be well tunable through the selection of organic and inorganic monomers. The organic monomers of a MOF can all be identical, or the MOF can be composed of two or more different organic monomers with nearly identical framework coordination functional group configurations. The latter are called "mixed-linker MOFs." Similarly, the inorganic monomers of a MOF can also be identical, or they can be different, in which case they are called "mixed-metal MOFs."

[0019] MOFs can be crystalline, amorphous, or have a deformable structure. MOFs made from structurally rigid monomers tend to form repeating three-dimensional networks characterized by permanent porosity, i.e., they are crystalline. Such crystalline MOFs are characterized by numerous pores. As used herein, the term "pore" refers to any type of opening, cavity, channel, or hole within the MOF network. MOFs can contain pores of various shapes in different proportions based on the MOF's crystalline structure. However, the pores of a particular MOF are generally very similar to each other in terms of size and chemical environment.

[0020] The organic monomers of MOFs may contain functional groups that do not directly interact with the inorganic monomers to form the MOF network. In this disclosure, such functional groups are referred to as "free" functional groups. When such functional groups are present in a crystalline MOF, they can be introduced into the pores of the MOF to form sites for adsorption, coordination, and / or chelation of guest ions or molecules. The exact nature of such sites depends on the network topology of the MOF and the type and number of functional groups introduced into the pores. By selecting appropriate MOFs in terms of free functional groups, specific chelating sites, such as within the pores, can be constructed for strong and selective adsorption, coordination, and / or chelation of specific compounds. As used herein, the terms "chelating" and "chelation" refer to the coordination, complexation, and / or binding of a metal, e.g., a radionuclide cation, by at least two ligands. The term "ligand" refers to a moiety, eg, a molecule, a portion of a molecule, a functional group, etc., that is capable of coordinating, complexing and / or bonding to a metal.

[0021] Various functional groups can be used to modify the shape and charge balance of the chelating moieties. Because MOFs are constructed from coordinate bonds between organic and inorganic monomers, adding functional groups that can act as coordinating groups may produce undesired and / or unexpected products during MOF preparation. Therefore, the introduction of free functional groups into MOFs requires careful design.

[0022] In the present invention, particles of certain types of MOFs are used as carriers for specific radionuclides suitable for use in imaging, providing new radiolabeled tracers. As further disclosed below, suitable radionuclides are short-lived gamma-emitting radionuclides or positron-emitting radionuclides. The MOFs used in the present invention are crystalline MOFs containing potentially metal-coordinating free functional groups extending into the pores of the MOF in such a manner that the free functional groups can coordinate and / or bind to short-lived radionuclides, such as radionuclide cations. Thus, each pore of these MOFs has the ability to function as a chelating macroligand for radionuclides. MOF particles represent a new class of carriers and may have the ability to contain radioisotopes with little or no leakage. Thus, it has now been discovered that MOFs suitable for carrying effective radioisotopes for use in therapy, typically alpha-emitting nuclides, are also useful as carriers of short-lived radionuclides for use in imaging. Using the same MOF carrier for various radioisotopes for imaging and therapy ensures nearly identical biodistribution of MOF carriers containing imaging agents (such as gamma-emitting nuclides) and therapeutic agents (such as radium-223), and this approach may enable pretreatment screening of patients to predict response to therapy and prevent unnecessary treatment of non-responders.

[0023] Thus, in one aspect, the present invention relates to a particle comprising a MOF, wherein the MOF comprises a repeating three-dimensional network of inorganic and organic monomers forming pores, the pores are designed for chelating short-lived radionuclides, and the particle comprises a radionuclide located within at least one of the pores. Optionally, the particle comprises at least one targeting moiety. Thus, in one embodiment, the particle comprises at least one targeting moiety attached to the particle on the outer surface of the particle.

[0024] In some embodiments, the present invention relates to a particle, the particle comprising: a repeating three-dimensional network of inorganic and organic monomers that forms pores; and at least one free functional group extending into the pore, the free functional group being selected from the group including carboxylic acid, carboxylate, hydroxyl, sulfonic acid, sulfonate, sulfhydryl, primary amine, secondary amine, and combinations thereof; MOFs containing; Optionally, at least one targeting moiety linked to the particle on the outer surface of the particle; and at least one short-lived radionuclide; Including, wherein said at least one radionuclide is located in at least one of the pores.

[0025] In one embodiment, at least one targeting moiety is linked to the particle on the exterior surface of the particle.

[0026] FIG. 1 shows a schematic representation of a non-limiting embodiment of a particle 1 of the present invention comprising a MOF 2 that forms a pore 3 and has a functional group 4 extending into the pore 3, where the particle 1 comprises a targeting moiety 5, shown here as an antibody, and a radionuclide 6 is located within the pore 3.

[0027] The MOF particles of the present invention contain at least one short-lived radionuclide. As used herein, the term "radionuclide," which may also be referred to as a radionuclide, radioisotope, or radio-emitting isotope, refers to an unstable atom with excess nuclear energy. Generally, this excess energy can be utilized in one of three ways: emitted from the nucleus as gamma rays, transferred to one electron and emitted as a conversion electron, or used to generate and emit a new particle (alpha particle or beta particle) from the nucleus. During these processes, the radionuclide is said to undergo radioactive decay. The resulting nuclide is called a daughter nuclide or progeny nuclide. The radionuclide contained in the particles of the present invention is a short-lived radionuclide suitable for use as a radiotracer, i.e., an imaging agent. In some embodiments, the at least one radionuclide is a gamma-ray-emitting radionuclide or a positron-emitting radionuclide. A positron-emitting nuclide interacts with a nearby electron, resulting in the simultaneous emission of two gamma rays in opposite directions. In one embodiment, the at least one radionuclide of the present invention is a gamma-ray-emitting nuclide, where gamma-ray-emitting nuclide as used herein may also include a positron-emitting nuclide. A diagnostic radioisotope must be capable of emitting gamma rays and contain sufficient energy to escape from the body. Ideally, the decay rate of the radioisotope should be complete fairly quickly after imaging, i.e., short-lived. In one embodiment, the radionuclide has a half-life of 0.5 hours to 60 days, for example, 5 hours to 60 days, for example, 1 to 20 days, for example, 1 to 5 days, for example, 3 to 5 days.

[0028] At least one radionuclide is located within the pore, e.g. by being present within, e.g. surrounded by, the pore, and is preferably coordinated to and / or chelated by at least one free functional group extending into said pore.

[0029] Preferably, the radionuclide is a radioactive cation. More preferably, the radionuclide is a radionuclide selected from the group including Ga-68, Ti-45, Tc-99m, Ba-133m, F-18, In-111, Ga-67, Zr-89, Ba-131, Yb-169, and Sc-43. In some embodiments, the radionuclide is selected from the group including Zr-89, F-18, and Ga-67. When F-18 is used, the isotope is not itself cationic, but rather is, for example, aluminum-[ 18 F] fluoride ([ 18 F]AlF2 + ) complexes. Thus, radiolabeled AlF2 + will bind to the MOF as a cation. In the case of Tc-99m, the isotope is not readily available as a cation in aqueous solution by itself, but rather, for example, [Tc(H2O)3(CO)3] + It may form part of a cationic phase such as

[0030] Suitable radionuclides have relatively short half-lives, are compatible with imaging procedures and clinical administration, and therefore have good diagnostic potential, as described below for each isotope (see Table 1). These radionuclide cations described above can bind strongly to the negatively charged chelating groups of MOFs, limiting leakage of the radioisotopes that would otherwise occur in vivo due to competition with salts and other components. Daughter isotopes of these radioisotopes can also be captured and retained in these MOFs. The half-life of a radionuclide must be long enough to allow purification, transportation, pharmaceutical synthesis, and administration before too much activity is lost. However, a half-life that is too long can result in a substantial increase in the dosage required to achieve efficacy, increasing the risk of chemical toxicity and accumulation of radioactivity in tissues.

[0031] [Table 1]

[0032] In some embodiments, the particles contain one radionuclide. In other embodiments, the particles contain more than one radionuclide, for example, two, three, or five, independently selected from the group including the short-lived radionuclides described above. When the particles contain more than one radionuclide, the radionuclides are typically disposed in separate pores, although the presence of two radionuclides in the same pore may also be possible. It should be noted that in all embodiments, complete control of the number of radionuclides per particle cannot be expected. During the chelation process, in which the particles are contacted with a solution containing the radionuclides, a statistical distribution of radionuclides per particle will occur.

[0033] The MOFs of the present invention comprise a repeating three-dimensional network of inorganic and organic monomers, i.e., they are crystalline. The organization of the inorganic and organic monomers in the repeating three-dimensional network results in the formation of pores. That is, the rigidity and set geometry of the inorganic and organic monomers result in a set spatial separation between specific monomers, resulting in the formation of pores. MOFs with free functional groups can be understood to have somewhat dynamic pore sizes due to the freedom of orientation of the free functional groups. Pore size can be measured, for example, by the "inclusion sphere," i.e., the largest sphere that can be placed within the pore without contacting the van der Waals surface of the MOF. The size of the pore opening, also referred to as the "window size," can be measured by the "diffusion sphere," i.e., the smallest sphere that can move within the structure. MOFs for use in the present invention advantageously have inclusion sphere pore sizes of 0.3 to 3 nm, preferably 0.5 to 1.5 nm. Furthermore, the MOFs of the present invention have pore windows of a certain size, preferably diffusion spheres with a diameter of at least 3 Å, that allow the adsorption of radionuclides. The pore size can be controlled by the size, structure, and bonding of the inorganic and organic monomers. The pores can be of any shape, including, but not limited to, tetrahedrons, octahedrons, and hexahedrons.

[0034] Of the approximately 100,000 or more MOF structures reported, only a limited number can be utilized in the present invention. Useful MOFs are essentially limited by their pore topology and the MOF's ability to accommodate functional groups on linkers that point into the pore instead of being attached to inorganic monomers (or by post-synthetic incorporation onto either the linker or the inorganic cluster). The MOF's pore topology must allow the diffusion of radioactive ions from the outside into the pore, and the pore must be large enough to accommodate functional groups and adsorbed radioactive cations. Examples of MOF structures that fit this description include, for example, the list of MOFs provided herein. Suitable pore sizes and pore window sizes are described above.

[0035] Because radioactive cations are adsorbed into negatively charged pockets in MOFs, the aforementioned functional groups should have a negative or partially negative polarity in an aqueous environment at physiological pH. A list of such functional groups is provided herein. In some cases, such functional groups are directly accessible following MOF synthesis, such as UiO-66(COOH)2 and UiO-66-NH2, with the carboxylate and amine groups pointing into the pore, respectively. In some cases, the functional groups are accessible through post-synthetic modification; for example, ZIF-90, which contains an aldehyde group pointing into the appropriate pore, can be converted to ZIF-8-COOH by reaction with hydrogen peroxide. In other cases, the functional groups are incorporated onto inorganic monomers, such as the introduction of a free imidazolate group into MOF-808 by reaction with histidine.

[0036] In one embodiment, MOFs based on Zr(IV), Hf(IV), Ce(IV), Fe(III), Al(III), Ti(IV), or Cr(III) with carboxylate organic monomers, or MOFs based on Zn(II) imidazolate, are included in the particles, which are known to be stable in aqueous media and therefore may be particularly useful in the present invention.

[0037] An example of a preferred MOF is terephthalate (C6H4(COO)2 2- ) Cationic hexanionic zirconium cluster Zr6O4(OH)4 as organic and inorganic monomers 12+ and the corresponding hafnium and cerium derivatives of UiO-66, Hf-UiO-66 and Ce-UiO-66 (Hf6O4(OH)4, respectively). 12+ and Ce6O4(OH)4 12+ Another example of a zirconium-based MOF is MOF-808, C24H16O32Zr6, which contains a benzene-1,3,5-tricarboxylic acid linker. UiO-66, Hf-UiO-66, and other MOFs with the same topology (network shape), known as the fcu network topology, contain tetrahedral and octahedral pores, with a dynamic ratio of 2:1 between the former and the latter. Each tetrahedral pore contains four corners where three organic linkers "meet," i.e., extend toward the same spatial volume, and each octahedral pore contains six corners where four organic linkers "meet." In their most stable conformation, the free functional groups are oriented toward the corners of the octahedral pore, but dynamic rotation around the linker axis and steric repulsion between adjacent carboxylate groups can often direct the free functional groups into the tetrahedral pore as well.

[0038] Figure 2 shows a schematic diagram of a network structure with the fcu topology, where inorganic monomers are shown as spheres with a cuboctahedral coordination geometry and organic monomers as bridging rods. Figure 3 shows the octahedral (O) and tetrahedral (T) pores of the fcuMOF. The large transparent spheres indicate the size of each pore.

[0039] M(IV)-based MOFs, where M = Zr and / or Hf, i.e., MOFs in which the inorganic monomers are based on the metals Zr and / or Hf in the +4 (M(IV)) oxidation state, and which have carboxylate-based organic monomers, such as UiO-66, Hf-UiO-66, and their derivatives, are believed to be particularly suitable for in vivo applications for several reasons: (1) the monomers may have advantageously low toxicity in vivo; (2) the MOFs may exhibit excellent stability in aqueous solutions, such as human serum, due to the stability of the M(IV)-carboxylate bond against hydrolysis, as shown in Examples 2 and 3; and (3) the M(IV) oxocluster inorganic monomers may have high connectivity, i.e., a large number of organic monomers may be linked together such that the free functional groups of several organic monomers are in spatial proximity (which may enable the formation of highly coordinated chelating sites adjacent to the cluster). As a result, the MOF particles of the present invention are particularly stable and efficient carriers for radionuclides, which may have very high adsorption capacities and allow specific imaging with negligible leakage into other organs.

[0040] Mixed-metal and / or mixed-linker derivatives of UiO-66 are also expected to exhibit advantageous properties similar to those of UiO-66. Related mixed-metal derivatives include derivatives containing two or more metals from the group including or consisting of Zr(IV), Ce(IV), and Hf(IV) in inorganic monomers. Related mixed-linker derivatives include derivatives containing monomers known to those skilled in the art to have coordination geometries similar to terephthalates, such as monomers selected from the group including or consisting of aminoterephthalate, hydroxyterephthalate, mellitate, pyromellitate, sulfoterephthalate, muconate, and combinations thereof. Suitable mixed-linker MOFs can be obtained by multiple linker synthesis or by linker exchange, both of which are well known to those skilled in the art.

[0041] Additionally, MOFs with inorganic monomers based on Fe(III), Al(III), Ti(IV), and / or Cr(III) may also be particularly useful in the present invention. The organic monomers may be selected from the group including or consisting of, for example, terephthalate, aminoterephthalate, hydroxyterephthalate, mellitate, pyromellitate, sulfoterephthalate, muconate, and combinations thereof. While the MOFs may not form the same topology as UiO-66, they may form other interesting topologies that may function in the same manner.

[0042] The MOFs of the present invention comprise at least one free functional group extending into the pores. Preferably, the MOFs comprise a repeating three-dimensional network of inorganic and organic monomers that form pores, with at least one free functional group extending into each pore (i.e., each pore has at least one free functional group extending therein). In some embodiments, only a certain amount of the pores, such as 50% of the pores, e.g., 80% of the pores, e.g., 95% of the pores, e.g., 100% of the pores, have at least one free functional group extending therein.

[0043] As used herein, the term "extending into a pore" means that the functional group is directed, oriented, and / or present in one of the pores formed by the repeating three-dimensional network of inorganic and organic monomers. Thus, the free functional group is available within the pore to coordinate, bind, and / or react with compounds, ions, and the like. In particular, the functional group is available to coordinate, complex, and / or bind to a radionuclide, e.g., a radionuclide cation.

[0044] At least one free functional group is bonded to an inorganic monomer and / or an organic monomer. When at least one free functional group is linked to an organic monomer, it is preferably covalently bonded to the organic monomer. In some embodiments, each organic monomer of the MOF has at least one free functional group linked thereto. In other embodiments, a predetermined amount of organic monomers each have at least one free functional group linked thereto. In some embodiments, each inorganic monomer of the MOF has at least one free functional group linked thereto. In other embodiments, a predetermined amount of inorganic monomers each have at least one free functional group connected thereto.

[0045] The free functional groups are preferably Lewis basic and are selected from the group including or consisting of carboxylic acids, carboxylates, hydroxyls, sulfonic acids, sulfonates, sulfhydryls, primary amines, secondary amines, and combinations thereof. Secondary amines are selected from the group including or consisting of amines of the general structural formula -NHR, where R is selected from the group including or consisting of C1-C8 alkyls, alkenyls, and alkynyls having at least one Lewis basic functional group (e.g., carboxylic acids, carboxylates, hydroxyls, sulfhydryls, sulfonic acids, sulfonates, primary amines, secondary amines, and combinations thereof), such as C1-C4 linear and branched alkyls, alkenyls, and alkynyls having at least one Lewis basic functional group (e.g., carboxylic acids, carboxylates, hydroxyls, sulfonic acids, sulfonates, sulfhydryls, primary amines, secondary amines, and combinations thereof). Such functionality can be obtained, for example, by performing a peptide condensation between an N-protected natural amino acid and the free primary amino group of the organic monomer of the MOF.

[0046] The free functional groups may be advantageously selected based on the choice of radionuclide. For example, if the radionuclide is known to those skilled in the art to be acidophilic, or "hard" according to the HSAB theory (hard and soft (Lewis) acids and bases), the pore may advantageously comprise at least one oxygen-containing functional group, i.e., carboxylic acid, carboxylate, hydroxyl, sulfhydryl, sulfonic acid and / or sulfonate. Correspondingly, if the radionuclide is "soft" according to the HSAB theory, the pore may advantageously comprise at least one amine group.

[0047] Thus, in some embodiments, the MOF comprises at least one free functional group selected from the group comprising or consisting of carboxylic acid, carboxylate, hydroxyl, sulfonic acid, sulfonate, sulfhydryl, primary amine, secondary amine, and combinations thereof. In other embodiments, the MOF comprises at least one free functional group selected from the group comprising or consisting of carboxylic acid, carboxylate, hydroxyl, sulfonic acid, sulfhydryl, sulfonate, and combinations thereof. In still other embodiments, the MOF comprises at least one free functional group selected from the group comprising or consisting of primary amine and secondary amine, and combinations thereof.

[0048] Preferably, the MOF comprises 1 to 4 free functional groups, for example 1 to 2 functional groups, for example at least 3, for example at least 4 free functional groups. In some embodiments, the MOF comprises at least 2 free functional groups, and the free functional groups are the same, or at least 2, for example at least 3, for example all, of the free functional groups are different from each other. In some embodiments, the MOF comprises at least 3 free functional groups, and the free functional groups are the same, or at least 2, for example at least 3, for example all, of the free functional groups are different from each other. In some embodiments, the MOF comprises at least 4 free functional groups, and the free functional groups are the same, or at least 2, for example at least 3, for example all, of the free functional groups are different from each other.

[0049] When the MOF comprises at least two free functional groups as disclosed above, the structure of the MOF can be selected to allow some or all of the at least two free functional groups to point toward a common spatial volume, such as a common point or volume within the pore. When the MOF comprises at least two free functional groups as disclosed above, the structure of the MOF can be selected to allow some or all of the at least two free functional groups to orient in a manner that allows for favorable interactions with the radionuclide cation in the presence of the radionuclide cation, such as by aligning with the outer orbital of the radionuclide cation. In some embodiments, each free functional group has a distance of 4 to 15 Å, e.g., 4 to 12 Å, e.g., 5 to 10 Å, from at least one, e.g., all, of the other free functional groups extending into the same pore.

[0050] Furthermore, the selection and placement of the at least one free functional group can be used to alter the geometry of the coordination, e.g., binding, e.g., chelation, etc., site within the pore. Such sites can be formed by the presence of one or more free functional groups, but can also result from the size and / or shape of the pore. In some embodiments, such sites are defined as including all free functional groups extending into the same pore. In some embodiments, such sites are defined as including free functional groups extending into the same pore and having a maximum distance of no more than 15 Å, e.g., 10 Å, from at least one other free functional group within the same pore. In some embodiments, such sites are present at the corners of the pore. This placement may entail that the site is only accessible from one direction, thus limiting competitive adsorption. Furthermore, if such sites are present at the corners of the pore or otherwise within the interior of the pore opposite the pore opening, other compounds, e.g., other cations, e.g., competing cations, may be present within the pore and sterically block the radionuclide from leaving the pore. Such corner sites can, in principle, be constructed in all MOFs capable of containing free functional groups, including Cr-MIL-100, Fe-MIL-100, and Al-MIL-100, Cr-MIL-53, Fe-MIL-53, and Al-MIL-53, Zr-MIL-140, Hf-MIL-140, Zr-MOF-711, Hf-MOF-711, ZIF-8, Ti-MIL-125, and MOF-808.

[0051] Examples of coordination, binding, and / or chelation sites are shown in Figures 4-7. Figure 4 shows an example of a coordination, binding, and / or chelation site at the corner of a tetrahedral cage with three free carboxylate groups pointing into the pore. Figure 5 shows an example of such a site at the corner of an octahedral pore with four free carboxylate groups pointing into the pore. Figure 6 shows such a site at the corner of an octahedral pore with two free carboxylate groups and two free amide groups pointing into the pore. The latter can be obtained, for example, by post-synthetic peptide condensation on free primary amino groups. Post-synthetic modifications are discussed below. Figure 7 shows such a site at the corner of an octahedral cage with two free carboxylate groups and two free amide groups pointing into the pore, one of which carries a DOTA chelator. Figure 8 shows a pore with multiple free functional groups extending into the pore.

[0052] Furthermore, at least one functional group directed into the pore can be used to alter the charge balance of the pore and / or the charge balance of sites for coordination, e.g., binding, e.g., chelation, etc., within the pore. Advantageously, the MOFs of the present invention contain a free functional group, or combination of functional groups, that results in a net negative charge within the pore. This net negative charge may promote strong, selective adsorption of cations.

[0053] Introduction of substituents onto the phenyl ring of the terephthalic acid monomer of UiO-66 and UiO-66-type MOFs provides easy access to crystalline MOFs containing at least one free functional group extending into the pore, where the at least one free functional group is selected from the group including carboxylic acid, carboxylate, hydroxyl, sulfonic acid, sulfonate, sulfhydryl, primary amine, secondary amine, and combinations thereof. For example, UiO-66-COOH, UiO-66(COOH)2, and UiO-66-NH2 are all commercially available. UiO-66-COOH, UIO-66(COOH)2, Hf-UiO-66-COOH, and Hf-UIO-66(COOH)2 represent preferred MOFs with 6–12 free carboxylic acid functional groups extending into their pores, of which 3 or 4 free functional groups form coordination sites within the pore and thus can chelate radionuclide cations in an efficient and / or stable manner.

[0054] There are two main approaches to so-called pore engineering, i.e., the introduction of free functional groups extending into the pores. These include the synthesis of MOFs using "preintegrated organic monomers," which contain two different coordination sites for framework construction and other applications, and "postsynthetic modification," in which additional functional groups are sequentially attached to preassembled MOFs. Free functional groups in MOFs can be modified by chemical reactions commonly referred to as "postsynthetic modification." In principle, any chemical reaction that can be performed by standard wet chemistry techniques can be performed on the same functional group in a MOF. For example, amino acids can be reacted with free primary amine groups in a MOF by peptide condensation reactions. Using this method, molecules with specific properties can be grafted onto MOFs, such as into their pores. Therefore, MOFs with specific structures and specific free functional groups can be obtained by both designing and synthesizing new MOFs and modifying existing ones. Thus, various derivatives of MOFs having the UiO-66 structure, as well as MOFs having other structures and containing various free functional groups, are readily available. In some embodiments, at least one radionuclide chelator known to those skilled in the art, such as EDTA, e.g., DOTA, is grafted onto the group extending into the pore, such that at least one free functional group is a known chelator.

[0055] Furthermore, most MOFs can tolerate a percentage of linker-deficient defects, i.e., sites where an organic linker is missing from the structure, leaving a coordinatively unsaturated site on the adjacent inorganic monomer. These unsaturated sites can be modified with coordinating molecules, such as molecules with at least one functional group that can coordinate inorganic monomers and contribute to the functional properties of the MOF, such as amino acids, that have a free functional group for extending into the pore.

[0056] Preferably, the MOFs of the present invention consist of a repeating three-dimensional network of inorganic and organic monomers that form pores, and at least one free carboxylic acid or carboxylate functional group extending into each pore.

[0057] Figures 9, 10, and 11 show schematic diagrams of preferred MOFs. Figures 9 and 10 show partial crystal structures of M(IV)- and M(III)-based terephthalic acid MOFs. Figure 9 shows UiO-66 (organic monomers are shown as rods with each C / O atom positioned at a corner, and inorganic monomers are shown as polyhedra). Figure 10 shows MIL-53, where available pore space is shown as large spheres in addition to lines and polyhedra.

[0058] Preferred MOFs shown in Figures 9 and 10 may have an M(IV) inorganic monomer. Suitable organic monomers are shown below (structures I, II, III, IV, V, and VI): TIFF2025537706000003.tif195155

[0059] Structure I represents terephthalic acid / terephthalate organic monomers, which can form MOFs with M(III) and M(IV)-based inorganic monomers via metal-carboxylate bonds. 11 , R 12 , R 13 , and R 14 may each independently be selected from the group including or consisting of hydrogen, carboxylic acid, carboxylate, hydroxyl, sulfonic acid, sulfonate, sulfhydryl, primary amine, and secondary amine, i.e., each of the R groups may be hydrogen or a free functional group.

[0060] Structure II represents the biphenyl-4,4'-dicarboxylic acid organic monomer, which can form MOFs with M(III) and M(IV)-based inorganic monomers via metal-carboxylate bonds. 21 , R 22 , R 23 , R 24 , R25 , R 26 , R 27 and R 28 may each independently be selected from the group including or consisting of hydrogen, carboxylic acid, carboxylate, hydroxyl, sulfonic acid, sulfonate, sulfhydryl, primary amine, and secondary amine, i.e., each of the R groups may be hydrogen or a free functional group.

[0061] Structure III represents trimesic acid (1,3,5-benzenetricarboxylic acid) organic monomer, which can form MOFs with M(III) and M(IV)-based inorganic monomers via metal-carboxylate bonds. 31 , R 32 and R 33 may each independently be selected from the group including or consisting of hydrogen, carboxylic acid, carboxylate, hydroxyl, sulfonic acid, sulfonate, sulfhydryl, primary amine, and secondary amine, i.e., each of the R groups may be hydrogen or a free functional group.

[0062] Structure IV represents an adipic acid organic monomer, which can form MOFs with M(III) and M(IV)-based inorganic monomers via metal-carboxylate bonds. 41 , R 42 , R 43 and R 44 may each independently be selected from the group including or consisting of hydrogen, carboxylic acid, carboxylate, hydroxyl, sulfonic acid, sulfonate, sulfhydryl, primary amine, and secondary amine, i.e., each of the R groups may be hydrogen or a free functional group.

[0063] Structure V represents a 1,4-cyclohexyldicarboxylic acid organic monomer, which can form MOFs with M(III) and M(IV)-based inorganic monomers via metal-carboxylate bonds. 61 , R 62 , R 63 , R 64 , R 65 , R 66 , R67 , R 68 , R 69 and R 70 may each independently be selected from the group including or consisting of hydrogen, carboxylic acid, carboxylate, hydroxyl, sulfonic acid, sulfonate, sulfhydryl, primary amine, and secondary amine, i.e., each of the R groups may be hydrogen or a free functional group.

[0064] Structure VI represents a naphthyl organic monomer, which can form MOFs with M(III) and M(IV)-based inorganic monomers via a metal-carboxylate bond. 71 , R 72 , R 73 , R 74 , R 75 and R 76 may each independently be selected from the group including or consisting of hydrogen, carboxylic acid, carboxylate, hydroxyl, sulfonic acid, sulfonate, sulfhydryl, primary amine, and secondary amine, i.e., each of the R groups may be hydrogen or a free functional group.

[0065] In each of structures I-VI, the secondary amine can be selected from the group including or consisting of amines of the general structural formula -NHR, where R is selected from the group including or consisting of C1-C8 alkyl, alkenyl, and alkynyl having at least one Lewis basic functional group (e.g., carboxylic acid, carboxylate, hydroxyl, sulfhydryl, sulfonic acid, sulfonate, sulfhydryl, primary amine, secondary amine, and combinations thereof), such as C1-C4 straight-chain and branched alkyl, alkenyl, and alkynyl having at least one Lewis basic functional group (e.g., carboxylic acid, carboxylate, hydroxyl, sulfhydryl, sulfonic acid, sulfhydryl, primary amine, secondary amine, and combinations thereof).

[0066] Figure 11 shows a MOF with a zeolitic imidazolate framework and the so-called sod topology, where the organic monomers are shown as balls and sticks representing atoms and bonds, and the Zn atoms are shown as tetrahedra.

[0067] A preferred MOF shown in Figure 11 may have an M(II) inorganic monomer. A suitable organic monomer is shown below (Structure VII): TIFF2025537706000004.tif4345

[0068] Structure VII represents an imidazole organic monomer, which can form MOFs (also known as ZIFs) with M(II)-based inorganic monomers via metal-imide bonds. 51 , R 52 and R 53 can each independently be selected from the group including or consisting of hydrogen, carboxylic acid, carboxylate, hydroxyl, sulfonic acid, sulfonate, sulfhydryl, primary amine, and secondary amine, i.e., each R group can be hydrogen or a free functional group. Secondary amines can be selected from the group including or consisting of amines of the general structural formula -NHR, where R is selected from the group including or consisting of C1-C8 alkyl, alkenyl, and alkynyl having at least one Lewis basic functional group (e.g., carboxylic acid, carboxylate, hydroxyl, sulfhydryl, sulfonic acid, sulfonate, primary amine, secondary amine, and combinations thereof), such as C1-C4 linear and branched alkyl, alkenyl, and alkynyl having at least one Lewis basic functional group (e.g., carboxylic acid, carboxylate, hydroxyl, sulfonic acid, sulfonate, sulfhydryl, primary amine, secondary amine, and combinations thereof).

[0069] In the inventions disclosed herein, MOFs exist in the form of particles, such as microparticles or nanoparticles. Preferably, the particles are nanoparticles. As used herein, the term "nanoparticle" refers to any particle having a diameter less than 1000 nm, e.g., 1-1000 nm. Similarly, the term "nanoparticle" refers to a plurality of particles having an average diameter of about 1-1000 nm. References to the "size" of nanoparticles refer to the length of the nanoparticle's largest linear dimension. For example, the size of a perfectly spherical nanoparticle is its diameter. Size may refer to the hydrodynamic radius of the particle, as characterized by, for example, dynamic light scattering. In some embodiments, the nanoparticles of the present invention have a particle diameter of 1-200 nm. Correspondingly, the term "microparticle" refers to a particle having a diameter less than 1000 μm, e.g., 1-1000 μm.

[0070] Microparticles and nanoparticles have also been used in radiopharmaceuticals. When such particles are used, a key factor is their stability, both in the sense that the particles themselves should be completely stable or slowly degrade to reduce the risk of system toxicity, and in the sense that the radionuclides should be strongly bound to the particles to avoid leakage. The MOFs of the present invention are highly stable, as discovered by the inventors and shown in Examples 2 and 3. Furthermore, the presence of free functional groups, together with the confining effect of the pore itself, ensures strong chelation of the radionuclides to the particles, as shown in Example 7. The choice of free functional groups can result in a high level of selectivity, e.g., preferential chelation of cations over anions and / or hard ions over soft ions. Thus, the present invention provides a particularly stable carrier for radionuclides.

[0071] Throughout the MOF particles of the present invention, there are 10^3 to 10^5 pores that have the potential to capture radionuclide cations in a portion of them, i.e., the portion accessible from the outside of the particle. If a radionuclide cation is released from one pore, it can be captured by an adjacent pore, preventing leakage from the particle. This "readsorption" ability of desorbed radionuclide cations indicates that the MOF particles of the present invention can more efficiently retain radionuclide cations compared to conventional chelators. Furthermore, because the number of cations per particle can be adjusted, the level of radioactivity of the particle can be tuned.

[0072] Due to the presence of pores with suitable diffusion spheres and free functional groups extending into the pores, when the particles according to the invention are exposed to a solution containing radionuclide cations, these cations are easily adsorbed and chelated within the pores. A further advantage of using MOF particles according to the invention is that any competing species, such as other cations present in the solution, can occupy the missing pores rather than displacing the radionuclide cations.

[0073] When used for imaging, the signal-to-noise ratio of the particles of the present invention significantly exceeds that of conventional molecular contrast agents limited to one or a few gamma-ray-emitting nuclides. The particles have a high density of strong binding sites compatible with a wide range of alpha-, beta-, and gamma-ray-emitting nuclides and are highly capable of loading radiotracers. When used for therapy, MOFs, such as those for use in imaging disclosed herein, can be loaded with alpha- or beta-ray-emitting nuclides (as "MOF-drugs"), and for use in imaging, MOFs can be loaded with gamma- or positron-emitting nuclides (as "MOF-radiolatracers"). The universal loading concept and process allows for the use of a single particle platform for both imaging and therapy, eliminating the need for separate particle development for each purpose. Thus, the MOFs disclosed herein have been found to be useful as carriers of radionuclides for either therapeutic or imaging use.

[0074] In contrast to conventional molecular chelator approaches, the nanoparticle approach offers several key advantages. (1) Each particle can be loaded with the desired number of radioisotopes, allowing flexibility in radiation density / dose. (2) Its outer surface can be functionalized with multiple targeting antibodies, providing flexibility in avidity and unlocking the possibility of using various groups on the same particle to ensure multispecificity. (3) Radioisotopes occupy only a small number of the particle's uniform binding pores. Therefore, they can accept cations from their environment without competitive desorption of the radioisotope, and even if the radioisotope desorbs from its binding site, it is likely to be recaptured by an adjacent pore. (4) The particle's lattice structure provides a barrier that inhibits the release of daughter isotopes into the environment (Figure 1).

[0075] Therefore, the applicant plans to use the same MOF carrier for various types of radioisotopes for imaging and therapy, respectively, which will ensure identical biodistribution of imaging agents (including, for example, gamma-emitting nuclides) and therapeutic agents (including, for example, radium-223). This approach enables pretreatment screening of patients using the MOF-radiolatracer of the present invention to predict response to subsequent treatment with the MOF-drug and / or prevent unnecessary treatment of non-responders. A major challenge in targeted radiation therapy such as RIT is achieving ideal biodistribution, with colocalization of the drug and tumor, and ensuring specific radiation delivery to cancer cells. Every patient and cancer is unique and, despite common disease characteristics, cannot necessarily be treated with the same approach. The use of the particles and methods of the present invention, including the use of MOF-radiolatracers as imaging agents in subject prescreening, is expected to improve the selection of subjects who will respond to treatment containing the MOF-drug. Patients who do not meet the selection criteria established during diagnostic screening will not receive treatment, which could otherwise cause unnecessary side effects and loss of opportunity for alternative treatment options. Patients who meet the selection criteria can receive treatment, including treatment with an alpha-emitting agent, i.e., an MOF-agent, and are likely to respond favorably to the treatment. The selection criteria can be based, for example, on sufficient colocalization of the MOF-radioactive tracer and tumor, which is predictive of irradiation of cancer cells or cancer-bearing cells with the therapeutic MOF.

[0076] The MOFs and particles thereof of the present invention can be obtained by any method known to those skilled in the art, such as by synthesis in a commercially available manner, for example using any synthesis protocol available to those skilled in the art.

[0077] In some embodiments, the particle of the present invention comprises at least one target site connected to the particle on the outer surface of the particle.The term "external surface" used herein in relation to particle refers to its outer surface that corresponds to the surface of the pore in the particle.When the pore penetrates the particle and is visible in the particle, the outer surface is defined to include all surfaces of the outermost surface of the particle, but does not include the surface that defines the pore.

[0078] As used herein, the term "targeting moiety" refers to a moiety, such as a molecule, e.g., a portion of a molecule, that is "tissue-targeting," i.e., that serves to preferentially localize itself—and any moiety, such as a particle to which it is attached—to at least one tissue site where delivery of its presence, e.g., radioactive decay, is desired. The term "targeting moiety" can also refer to a functional group that serves to target or direct a particle to a specific location, cell type, diseased tissue, or association. A targeting moiety can be, for example, a moiety known to those skilled in the art to bind or complex to a biomarker, such as a cell surface marker, e.g., a receptor, transport protein, or cell adhesion molecule, present on diseased cells or cells in the vicinity of such cells. Such cell surface markers include, but are not limited to, proteins that are more highly expressed on diseased cell surfaces than on healthy cell surfaces, or proteins that are more highly expressed on cell surfaces during cell growth or replication than during quiescence. Moieties present in the vicinity of or associated with target cells or tissues can also be utilized in therapeutic targeting according to any embodiment of the present invention. For example, components present in or released from the matrix surrounding the target cells or tissue can be used for targeting if their presence, morphology, or concentration allows the region to be distinguished from healthy tissue.

[0079] Non-limiting examples of target sites include: carbohydrates; monosaccharides, such as glucose, mannose, galactose; urea derivatives; lipids; streptavidin; albumin; biotin; small molecule targeting moieties, such as steroid and non-steroid hormones; Aptamers, i.e., single-stranded oligonucleotides that recognize specific binding domains of receptors; Polymers such as biopolymers, e.g., antibodies; peptides, e.g., biomimetic peptides, e.g., phage-displayed peptides; proteins; nucleic acids; and cells, such as naturally occurring cells, e.g., genetically engineered cells Examples include:

[0080] Preferred targeting moieties include antibodies, antibody fragments, antibody constructs, constructs of antibody fragments, minibodies, nanobodies, intrabodies, unibodies, affibodies, and diabodies. As used herein, the term "antibody" refers to immunoglobulins, derivatives thereof that retain specific binding ability, and proteins having binding domains that are homologous or largely homologous to immunoglobulin binding domains. These proteins may be naturally occurring or partially or wholly synthetically produced. The term "antibody" encompasses, for example, monoclonal antibodies, polyclonal antibodies, recombinant antibodies, humanized antibodies, and / or chimeric antibodies. An antibody may be a member of any immunoglobulin class, including any of the human classes: IgG, IgM, IgA, IgD, and IgE. Examples of useful antibodies include conventional full-length antibodies (e.g., IgG) and camelid heavy chain antibodies (VHH).

[0081] As used herein, the term "antibody fragment" refers to any derivative of an antibody that is less than full-length. In exemplary embodiments, an antibody fragment retains at least a substantial portion of the full-length antibody's specific binding ability. Examples of antibody fragments include, but are not limited to, Fab, Fab', F(ab')2, scFv, Fv, dsFv diabody, and Fd fragments.

[0082] In some embodiments, the targeting moiety is one of two or more components that collectively have the effect of targeting the particles of the invention to a desired tissue. This is the case, for example, when one component binds to a specific tissue, tumor, or cell type (tissue-binding agent), and a second or additional component, the targeting moiety, binds to the tissue-binding agent. Suitable specific binding pairs for conferring mutual affinity between the tissue-binding agent and the targeting moiety are known in the art (e.g., biotin and avidin or streptavidin, etc.).

[0083] Targeting moieties can be obtained by any method known to those of skill in the art, e.g., commercially available, synthesized using any synthesis protocol available to those of skill in the art, e.g., produced enzymatically, synthetically and / or chemically.

[0084] In some embodiments, the particle contains only one targeting moiety. In other embodiments, the particle contains two or more targeting moieties, for example, five, for example, ten targeting moieties. The number of targeting moieties can be selected based on the size of the particle. The targeting moieties can be the same or different. The mass ratio of targeting moieties to particles can depend on the molecular weight of the targeting moieties and the diameter of the particles.

[0085] The use of two or more different targeting moieties has the advantage that more than one antigen can be targeted, resulting in improved binding to tissues or cells expressing the antigen profile associated with the target (e.g., M2 tumor-associated macrophages expressing CD163 and CD206). Another advantage would be the ability to target not only tumor-specific antigens but also blood vessels that accumulate at tumor sites (e.g., VCAM1).

[0086] At least one targeting moiety can be directly linked to the particle, for example, via a covalent bond, or at least one targeting moiety can be linked to the particle via a linking group. The targeting moiety can also be linked to the particle covalently conjugated with streptavidin, which strongly binds to biotin / biotin derivatives. Streptavidin can not only function as a linker but also as a binding site for the biotinylated moiety. Thus, streptavidin-conjugated particles can be bound to one or more biotinylated targeting moieties. Methods for linking targeting moieties to surfaces are well known in the art; for example, standard organic and / or inorganic chemistry, such as carbodiimide coupling, can be used. Suitable linking groups can be easily determined by those skilled in the art; for example, a range of linking groups is known from the field of antibody-drug conjugates. Non-limiting examples of linking groups include poly(ethylene glycol) (PEG), 2-(maleimidomethyl)-1,3-dioxane (MD), and maleimidocaproylsuccinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC). The exterior surface of MOF particles may be composed of the same organic functional groups as the interior of the pores and may undergo the same reactions. However, by using reagents that are sterically prohibited from entering the MOF pores, size discrimination can be used to perform reactions on the exterior surface rather than within the pores, thereby allowing for selective attachment of target moieties to the exterior surface of the particle.

[0087] At least one targeting site may be a targeting site for targeting cells suffering from a proliferative disease, such as tumor cells, cancer cells, cells suffering from a hyperplastic disease, or cells suffering from a neoplastic disease. In a preferred embodiment, the targeting site is a targeting site for targeting cancer cells. As used herein, the terms "cancer cell" and "tumor cell" refer to cells that divide at an abnormally increased rate. Cancer cells include, but are not limited to, carcinomas such as squamous cell carcinoma, non-small cell carcinoma (e.g., non-small cell lung cancer), small cell carcinoma (e.g., small cell lung cancer), basal cell carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, adenocarcinoma, papillary carcinoma, papillary adenocarcinoma, bladder adenocarcinoma, medullary carcinoma, undifferentiated carcinoma, bronchial carcinoma, melanoma, renal cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, cholangiocarcinoma, papillary carcinoma, transitional cell carcinoma, choriocarcinoma, seminal carcinoma, embryonal carcinoma, breast adenocarcinoma, gastrointestinal cancer, colon cancer, bladder cancer, prostate cancer, and squamous cell carcinoma of the neck and head region; e.g., fibrosarcoma, myxosarcoma, sarcoma ... These include sarcomas such as liposarcoma, chondrosarcoma, osteogenic sarcoma, chordal sarcoma, angiosarcoma, endothelial sarcoma, lymphangiosarcoma, synovial sarcoma, and mesothelial sarcoma; blood cancers such as myeloma, leukemia (e.g., acute myeloid leukemia, chronic lymphocytic leukemia, granulocytic leukemia, monocytic leukemia, lymphocytic leukemia, etc.), lymphoma (e.g., follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, malignant lymphoma, plasmacytoma, reticulum cell sarcoma, or Hodgkin's disease), and tumors of the nervous system, including glioma, glioblastoma multiforme, meningioma, medulloblastoma, schwannoma, and epididymoma. Those skilled in the art are familiar with targeting sites that can be used to target specific types of cells affected by proliferative diseases, especially cancer cells.

[0088] In another embodiment, the particles of the present invention do not contain targeting moieties. Whether drug substances are administered to the human body orally, intravenously, or parenterally, they are metabolized by metabolic enzymes in the hepatic portal system (liver), the site of most metabolism, and decompose the delivered substance so that it can be easily removed from the body. Therefore, the particles of the present invention that do not contain targeting moieties can be transported to the liver after administration to a subject and are well suited for liver imaging. Furthermore, the natural biological distribution of particles can be used to deliver radioisotopes to a given site and irradiate tissue in situ.

[0089] A particle as disclosed herein, i.e., a particle comprising a MOF, wherein the MOF comprises a repeating three-dimensional network of inorganic and organic monomers forming pores, and at least one free functional group extending into the pores, the functional group comprising a carboxylic acid, a carboxylate, a hydroxyl, a sulfonic acid, a sulfonate, a sulfhydryl, a primary amine, a secondary amine, and combinations thereof, wherein the particle optionally further comprises at least one targeting moiety linked to the particle on its exterior surface, and at least one radionuclide, wherein the at least one radionuclide is selected from the group of short-lived radionuclides as disclosed, and wherein the at least one radionuclide is located within at least one of the pores, the particle may have at least the following advantages over the prior art: (a) In contrast to existing small molecule chelators, MOF particles contain a large number of chelating sites, which may enable dose control by loading the particles with a predetermined number of radionuclides. (b) The network structure of MOFs can positively influence the ability of the particles to contain radiation, for example, by the following mechanisms: (1) In contrast to state-of-the-art molecular chelators, MOFs can contain, by physical adsorption, daughter isotopes that emerge through the decay chain of radionuclides and thus also retain the daughter isotopes in the vicinity of tumor cells. (2) In contrast to state-of-the-art molecular chelators, radionuclides adsorbed on MOFs are less susceptible to competitive adsorption by other ions because they can be adsorbed by the defective pores. (3) The desorbed radionuclide can be readsorbed into adjacent deletion pores.

[0090] In summary, the present invention may thus provide an improved imaging method.

[0091] Regarding (b)(2), competitive adsorption may be relevant not only during particle preparation and storage and during adsorption of radionuclide cations, but also when the particles are used as imaging agents.

[0092] The particles of the present invention may further comprise one or more molecules for modifying the particle's exterior surface. Such one or more molecules may be linked to the particle, e.g., coordinated, e.g., covalently bonded, etc., at the particle's exterior surface. Again, size discrimination may be used to conduct reactions on the exterior surface rather than within the pores. For example, the exterior surface of a MOF containing free carboxyl or amino groups may be functionalized with one or more compounds selected from the group consisting of PEG derivatives, N-hydroxysuccinimide (NHS), N-hydroxysulfosuccinimide (sulfo-NHS), MD linkers, Mal-PAB, and albumin to facilitate transport, prevent aggregation, and / or provide targeting functionality by increasing targeting flexibility and spatial distance between the MOF and its target. Albumin may be used to prevent aggregation and increase the particle's blood half-life.

[0093] The particles of the invention may further comprise one or more additional compounds, such as molecules, e.g., ions, located in at least one of the pores. Non-limiting examples include buffers and / or specific ions, e.g., ions to limit leakage of radionuclides due to steric hindrance.

[0094] MOF particles are typically produced by aqueous synthesis at 20-100°C, where solutions of appropriate inorganic precursors for inorganic monomers and organic monomers are mixed. In some cases, the organic monomers are dissolved directly in the inorganic precursor solution, or vice versa. In some cases, growth control factors (also called growth modulators) are added to influence the particle growth rate. MOF particles precipitate from solution as the structure forms. Published procedures for MOF production can be followed.

[0095] Targeting moieties can be attached, linked, or bonded—commonly referred to as conjugation—to the MOF particle directly or via a linker. For example: carboxyl MOFs can be conjugated to amine groups (present on the targeting unit) by carbodiimide (EDC, NHS / sulfo-NHS)-based crosslinking.

[0096] Radiolabeling can be carried out by uniformly mixing a solution or suspension of radionuclide cations with a suspension of particles for more than 1 minute, and then separating the remaining unbound radionuclide cations from the labeled particles, for example, by centrifugation or column purification. If the targeting site is present on the particle before radiolabeling is performed, the radiolabeling procedure can be more convenient, for example, in terms of time used, purification of the product, etc.

[0097] Thus, the particles of the present invention can be prepared by providing particles, e.g., nanoparticles, comprising a MOF, the process comprising: where MOF is a repeating three-dimensional network of inorganic and organic monomers that forms pores; and at least one free functional group extending into the pore, the functional group being selected from the group including carboxylic acid, carboxylate, hydroxyl, sulfonic acid, sulfonate, sulfhydryl, primary amine, secondary amine, and combinations thereof; wherein the particles optionally comprise At least one targeting moiety attached to the particle on the outer surface of the particle. and contacting said particles with a short-lived radionuclide; It can be prepared by

[0098] The radionuclide cation may be present in a composition that includes, for example, a liquid.

[0099] In another aspect, the present invention relates to a kit, said kit comprising: In the first container, a repeating three-dimensional network of inorganic and organic monomers that forms pores; and at least one free functional group extending into the pore, the functional group being selected from the group including carboxylic acid, carboxylate, hydroxyl, sulfonic acid, sulfonate, sulfhydryl, primary amine, secondary amine, and combinations thereof; MOFs containing; Optionally, at least one targeting moiety linked to the particle on the outer surface of the particle; and In the second container, short-lived radionuclides Includes:

[0100] Suitable radionuclides for use in this embodiment are as disclosed in the first embodiment.

[0101] Those skilled in the art will understand that the first container and the second container may further comprise a liquid, such as a solvent, for dissolving or suspending any components, as well as additional components, such as at least one carrier, diluent, and / or excipient.

[0102] The particles of the present invention comprising at least one short-lived radionuclide are intended for use in suitable imaging modalities, such as scintigraphy or positron emission tomography (PET). Scintigraphy and PET imaging using appropriate radiotracers enable functional or molecular-based imaging of disease. Such imaging can provide information about tumor metabolism, and can indicate which tumors are metabolically active and malignant, or which tumors have recurred. In some embodiments, the imaging modality is selected from the group comprising SPECT, PET and PET / CT imaging. In some embodiments, the imaging of the present invention using particles comprising MOFs loaded with short-lived radionuclides provides an assessment of metabolic function, and can be combined with other imaging modalities, such as X-ray, MR or ultrasound, for example, to image pathology.

[0103] The particles disclosed herein can be present as an active ingredient in a desired dosage unit formulation, such as a pharmaceutically acceptable composition containing a conventional pharmaceutically acceptable carrier. As used herein, the term "pharmaceutically acceptable" means that the compound must be physiologically acceptable to the recipient and, when part of a composition, compatible with the other components of the composition. The term "composition" refers to a mixture of one or more compounds according to the present invention and one or more additional chemical components in any formulation.

[0104] Thus, in another aspect, the present invention relates to a composition comprising at least one particle, wherein the at least one particle comprises a MOF, together with at least one pharmaceutically acceptable carrier, diluent and / or excipient; where MOF is a repeating three-dimensional network of inorganic and organic monomers that forms pores; and at least one free functional group extending into the pore, the functional group being selected from the group including carboxylic acid, carboxylate, hydroxyl, sulfonic acid, sulfonate, sulfhydryl, primary amine, secondary amine, and combinations thereof; Including, Here, the particles are Optionally, at least one targeting moiety attached to the particle on the outer surface of the particle; and At least one short-lived radionuclide Including, wherein at least one radionuclide is located within at least one of the pores.

[0105] The particle is defined as disclosed above. It may be a microparticle or a nanoparticle. Preferably, the particle is a nanoparticle.

[0106] The composition may be considered a pharmaceutical imaging agent composition because it comprises an active agent, i.e., particles, in combination with at least one pharmaceutically acceptable carrier, diluent and / or excipient, making the composition particularly suitable for use in diagnostic, e.g., imaging procedures.

[0107] The composition preferably comprises a plurality of particles of the present invention. The particles may be the same or different, i.e., with respect to the type and number of radionuclides and / or targeting moieties. In some embodiments, the composition is a particle suspension comprising monodisperse or polydisperse particles labeled with radionuclide cations.

[0108] The compositions may contain one or more of any conventional, pharmaceutically acceptable excipients and / or carriers, such as solvents, fillers, diluents, binders, lubricants, glidants, viscosity adjusters, surfactants, dispersants, disintegrants, emulsifiers, wetting agents, suspending agents, thickening agents, buffers, pH adjusters, absorption delaying agents, stabilizers, antioxidants, preservatives, antibacterial agents, antifungal agents, chelating agents, adjuvants, sweeteners, flavoring agents, and coloring agents, etc. Conventional formulation techniques known in the art, such as conventional mixing, dissolving, suspending, granulating, dragee-making, extruding, emulsifying, encapsulating, entrapping, or compressing processes, may be used to formulate the compositions.

[0109] In some embodiments, the composition is formulated for a particular method of administration to a subject.

[0110] The amount of particles according to the present invention present in the composition can vary. In some embodiments, the amount of particles according to the present invention present in the composition is 0.1 to 50% by weight, for example, 1 to 30% by weight, for example, 50 to 20% by weight. In other embodiments, the amount of particles according to the present invention present in the composition is 30 to 70% by weight, for example, 40 to 60% by weight. In still other embodiments, the amount of particles according to the present invention present in the composition is 50 to 100% by weight, for example, 50 to 70% by weight, for example, 50 to 80% by weight, for example, 60 to 98% by weight, for example, 70 to 95% by weight.

[0111] The composition may also include MOF particles that do not contain radionuclide cations, such as particles containing MOFs, where the MOFs comprise a repeating three-dimensional network of inorganic and organic monomers that form pores and at least one free functional group extending into the pores, where the functional group is selected from the group consisting of carboxylic acid, carboxylate, hydroxyl, sulfonic acid, sulfonate, sulfhydryl, primary amine, secondary amine, and combinations thereof, and the particles comprise at least one targeting site linked to the particle on its outer surface. Such particles may be the same as or different from the particles of the present invention except for the absence of radionuclide cations. The ratio between particles containing radionuclide cations and particles not containing radionuclide cations may vary. In a preferred embodiment, at least 90% of the particles contain radionuclide cations. The activity per mg of particle is typically in the range of 10 kBq to 900,000 MBq, e.g., 100 kBq to 900,000 MBq, or 100 kBq to 1000 MBq. This corresponds to a mass ratio (proportion of radioisotope per MOF) of up to 5% when using zirconium-89 (specifically 831,450 MBq) as an example.

[0112] Furthermore, the composition is substantially free of contaminants or impurities. In some embodiments, the level of contaminants or impurities other than residual solvent in the composition is less than about 5% by weight based on the total weight of the particles according to the present invention and other intended components. In certain embodiments, the level of contaminants or impurities other than residual solvent in the composition is less than about 2% or 1% by weight based on the total weight of the particles according to the present invention and other intended components.

[0113] In certain embodiments, the particles or compositions according to the invention are sterile. Sterilization can be achieved by any suitable method, including but not limited to, application of heat, chemicals, irradiation, high pressure, filtration, or a combination thereof.

[0114] The particles of the invention can be included in compositions and used as contrast agents. Thus, in another aspect, the invention provides particles for use as contrast agents, comprising: a repeating three-dimensional network of inorganic and organic monomers that forms pores; and at least one free functional group extending into the pore, the free functional group being selected from the group including carboxylic acid, carboxylate, hydroxyl, sulfonic acid, sulfonate, sulfhydryl, primary amine, secondary amine, and combinations thereof; MOFs containing; Optionally, at least one targeting moiety linked to the particle on the outer surface of the particle; and at least one short-lived radionuclide; Including, wherein said at least one radionuclide is located in at least one of the pores of said particle, Or a composition comprising said particles together with at least one pharmaceutically acceptable carrier, diluent and / or excipient.

[0115] The particles of the present invention and compositions containing the particles can be used diagnostically, such as for targeted delivery of radioactive decay to one or more specific sites in vivo, such as specific cells, tissues, or organs. The targeting moiety targets the particles to the specific site where radioactive decay, such as gamma-ray emission, is desired, and the MOF functions as a chelating agent with the advantageous properties described above. If the particles do not contain a targeting moiety, they will be transported to other organs, such as the liver, where the radioactivity will decay, depending on the biodistribution properties of the nanoparticles. Thus, in one embodiment, the particles can be used diagnostically for indications where nanoparticles are naturally transported, particularly liver cancer.

[0116] For the various aspects of the invention described herein relating to use as imaging agents and / or for imaging or diagnosing disease, particularly the selective targeting of diseased tissue, the diseased tissue may in all embodiments be present at a single site within the body (e.g., in the case of a localized solid tumor) or may be present at multiple sites (e.g., in the case of distributed or metastatic cancerous disease).

[0117] The particles and compositions of the invention may be particularly useful in imaging procedures, in diagnostic procedures, and in particular for imaging proliferative diseases. Thus, in a further aspect, the invention provides particles for use in diagnostic methods, a repeating three-dimensional network of inorganic and organic monomers that forms pores; and at least one free functional group extending into the pore, the functional group being selected from the group including carboxylic acid, carboxylate, hydroxyl, sulfonic acid, sulfonate, sulfhydryl, primary amine, secondary amine, and combinations thereof; MOFs containing; Optionally, at least one targeting moiety linked to the particle on the outer surface of the particle; and At least one short-lived radionuclide: Including, wherein said at least one radionuclide is located in at least one of the pores of said particle, Or a composition comprising said particles together with at least one pharmaceutically acceptable carrier, diluent and / or excipient.

[0118] In particular, in one embodiment, the particles or compositions comprising the particles are used in a method for diagnosing a proliferative disease in a subject. Such a diagnostic method may include imaging screening and biodistribution control. In particular, the diagnostic method includes evaluating information about the biodistribution and uptake of MOFs in relevant tissues of the subject, particularly proliferative tissues. This method can provide powerful insights into the distribution, binding, and other biological effects of MOF-containing particles. This approach allows the particles of the present invention to be used as imaging agents for pre-treatment screening of subjects, for example, to predict response to subsequent treatment using MOF-drugs and / or prevent unnecessary treatment of non-responders.

[0119] In one embodiment, the diagnostic method is followed by a subsequent treatment step using particles comprising the same MOF as used in the diagnosis, but carrying a therapeutic radionuclide. a repeating three-dimensional network of inorganic and organic monomers that forms pores; and at least one free functional group extending into the pore, the free functional group being selected from the group including carboxylic acid, carboxylate, hydroxyl, sulfonic acid, sulfonate, sulfhydryl, primary amine, secondary amine, and combinations thereof; MOFs containing; Optionally, at least one targeting moiety linked to the particle on the outer surface of the particle; and at least one radionuclide selected from the group comprising radium-223, radium-224, radium-225, bismuth-212, bismuth-213, lead-212, actinium-225, thorium-227, terbium-149 and terbium-161; Including, wherein the at least one radionuclide is located in at least one of the pores. This can be followed by a subsequent treatment with the particles.

[0120] Therefore, a diagnostic method using a MOF-radioactive tracer is followed by a treatment with a MOF-drug. The carrier MOF is preferably the same in the two steps, but the nucleotides carried are different, being gamma-emitting or positron-emitting nuclides, and alpha-emitting nuclides, respectively.

[0121] Particles are defined as disclosed herein and may be nanoparticles or microparticles, preferably nanoparticles.

[0122] As used herein, the terms "administer," "administration," and "administering" refer to (1) providing, giving, dispensing, and / or prescribing a formulation, preparation, or composition according to the present disclosure, either by or under the direction of a healthcare professional or their authorized representative, or by self-administration, and (2) the subject administering, ingesting, or consuming a formulation, preparation, or composition according to the present disclosure.

[0123] As used herein, "subject" means a human or non-human animal selected for treatment or therapy, and includes, and may be limited to, a "patient." Neither term should be construed as requiring the supervision (full or otherwise) of a medical professional (e.g., physician, nurse, nurse practitioner, physician assistant, orderly, clinical research associate, etc.) or a scientific researcher.

[0124] The subject is preferably a human subject. The subject may be male or female. In some embodiments, the subject is an adult (i.e., 18 years of age or older). In certain embodiments, the subject is elderly. In certain embodiments, the subject is not elderly. The subject is preferably a subject diagnosed with a proliferative disease, such as cancer.

[0125] The targeted diseased tissue may be a soft tissue site, a calcified tissue site, or multiple sites that are all soft tissue, multiple sites that are all calcified tissue, or may include at least one soft tissue site and / or at least one calcified tissue site. In one embodiment, at least one soft tissue site is targeted. The targeted site and the site of origin of the disease may be the same or different. If multiple sites are involved, this may include the site of origin or multiple secondary sites.

[0126] The term "soft tissue" is used herein to refer to tissue that does not contain a "hard," mineralized matrix. In particular, "soft tissue" as used herein can be any tissue that is not skeletal. Correspondingly, "soft tissue disease" as used herein refers to a disease that occurs in "soft tissue" as used herein. The present invention is particularly suited to the treatment of cancer, and thus "soft tissue disease" encompasses carcinomas, sarcomas, myelomas, leukemias, lymphomas, and mixed cancers that occur in any "soft" (i.e., non-mineralized) tissue, as well as other non-cancerous diseases of such tissues. Cancerous "soft tissue disease" includes solid tumors that arise in soft tissue, as well as metastatic tumors and micrometastatic tumors. In fact, a soft tissue disease may consist of a primary solid tumor of soft tissue and at least one metastatic tumor of soft tissue in the same patient. Alternatively, a "soft tissue disease" may consist solely of a solid tumor whose primary tumor is a skeletal disease, or solely of metastatic tumors.

[0127] When the particles or compositions of the present invention are used as imaging agents and / or in diagnostic methods according to the present invention, target sites may be selected based on particular biomarkers, such as antigens, expressed by or in the vicinity of tissues, cells or organs affected by a proliferative disease.

[0128] In some embodiments, the proliferative disorder is a cancer, a non-cancerous tumor, a neoplastic disorder, or a hyperplastic disorder.

[0129] In some preferred embodiments, the proliferative disease is cancer. As used herein, the terms "cancer" and "tumor" refer to any neoplastic growth in a subject, including primary tumors and metastases. Cancer can be of liquid or solid tumor type. Liquid tumors include tumors of hematological origin, including, for example, myeloma (e.g., multiple myeloma), leukemia (e.g., Waldenstrom syndrome, chronic lymphocytic leukemia, and other leukemias), and lymphomas (e.g., B-cell lymphoma, non-Hodgkin's lymphoma). Solid tumors can occur in organs, including, but not limited to, cancer of the lung, brain, breast, prostate, ovary, colon, kidney, and liver.

[0130] In some embodiments, the cancer is selected from the list comprising or consisting of lung cancer, pancreatic cancer, colorectal cancer; liver cancer, glioma, renal cancer, non-Hodgkin's lymphoma, neuroblastoma, CNS metastasis, peritoneal cancer, follicular lymphoma, colorectal cancer, small cell lung cancer, carcinoma, sarcoma, myeloma, leukemia, lymphoma, prostate cancer or mixed cancer.

[0131] In certain embodiments, the cancer is metastatic cancer. Treating metastatic cancer is notoriously difficult using conventional anti-cancer drug therapy, but the targeted MOF vehicle of the present invention represents a promising line of treatment for such cancers.

[0132] The targeting moiety of the particle will be selected based on the specific disease to be treated. For example, CD37 is highly expressed on B cells and the majority of B cell lymphomas, is absent on normal stem cells, and disappears again upon differentiation into plasma cells. Due to its high prevalence on the surface of B lymphomas, CD37 has become the target of several different drugs in clinical development. Therefore, anti-CD37 may be a useful targeting moiety for such cancers.

[0133] Non-Hodgkin's lymphoma spreads mainly through the lymphatic system, making it difficult to treat with conventional therapies (surgery, radiation). Furthermore, non-Hodgkin's lymphoma can metastasize to other tissue types, which is another reason why the present invention may be particularly effective against non-Hodgkin's lymphoma.

[0134] Furthermore, the present invention may also be useful for imaging chronic inflammatory diseases such as rheumatoid arthritis, psoriatic arthritis, inflammatory bowel diseases such as ulcerative colitis and / or Crohn's disease, and / or chronic obstructive pulmonary disease. Thus, in a further aspect, the present invention provides particles for use in a method for the diagnosis of chronic inflammatory diseases, a repeating three-dimensional network of inorganic and organic monomers that forms pores; and at least one free functional group extending into the pore, the functional group being selected from the group including carboxylic acid, carboxylate, hydroxyl, sulfonic acid, sulfonate, sulfhydryl, primary amine, secondary amine, and combinations thereof; MOFs containing; Optionally, at least one targeting moiety linked to the particle on the outer surface of the particle; and at least one short-lived radionuclide; Including, wherein said at least one radionuclide is located in at least one of the pores. particle, Or a composition comprising said particles together with at least one pharmaceutically acceptable carrier, diluent and / or excipient.

[0135] In these embodiments, the subject is preferably a subject diagnosed with a chronic inflammatory disease, such as rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, such as ulcerative colitis and / or Crohn's disease, and / or chronic obstructive pulmonary disease. The inflammatory process in the body plays an important role in injury control and repair. The inflammatory cascade, commonly referred to as inflammation, can take two basic forms: acute and chronic. Acute inflammation, part of the immune response, is the body's immediate response to injury or challenge due to physical trauma, infection, stress, or a combination of these three. Acute inflammation prevents further injury and promotes the healing and recovery process.

[0136] When inflammation becomes self-propagating, it becomes chronic or long-term. This is called chronic inflammation and continues beyond the actual injury, sometimes for months or years. Chronic inflammation can become a problem in itself, requiring medical intervention to control or prevent further inflammation-mediated damage. An imbalance between the pro- and anti-inflammatory components of the immune system can result in chronic inflammatory diseases. Rebalancing the immune system by killing inflammatory cells with radioisotope-loaded MOFs can prevent chronic inflammation and treat patients.

[0137] A particle or composition according to the present invention for use as an imaging agent and / or for use in a method of diagnosis comprises administering a therapeutically effective dose of the particle or composition to a subject. In one embodiment, the method or use comprises imaging a subject who has previously been administered an imaging agent. As used herein, the term "effective dose" refers to an amount of a particle according to the present invention effective to produce a desired imaging effect in a subject at a reasonable benefit / risk ratio. An effective dose may vary depending on the route of administration and dosage form. Furthermore, the dose may depend on the particle used, the type of radioactive decay of the radionuclide cation and / or its daughter nuclide, the stage of the condition, the age and weight of the subject, etc., and can be routinely determined by one of skill in the art according to principles well known in the art.

[0138] In some embodiments, the amount of radionuclide cation used per patient dose can be in the range of 1 kBq to 10 GBq, e.g., 1 MBq to 1 GBq, preferably 2 MBq to 400 MBq, more preferably 100 MBq to 400 MBq, and even more preferably 3 MBq to 400 MBq. Dosages and maximum doses can be determined by those skilled in the art based on general knowledge regarding appropriate dosages and maximum doses. It is recognized in the art that realistic and conservative estimates of toxic side effects of daughter isotopes must be employed.

[0139] In some embodiments, the particles are administered at a dose of 10 Bq to 100 MBq / kg body weight, e.g., 10 kBq to 10 MBq / kg body weight, e.g., 10 kBq to 4 MBq / kg body weight, preferably 50 kBq to 4 MBq / kg, e.g., 100 kBq to 2 MBq / kg, more preferably 75 kBq / kg, and particularly 4 to 6 MBq / kg. Correspondingly, a single dosage unit may contain anywhere within these ranges (e.g., a range of 100 kBq to 10 GBq per dosage) multiplied by an appropriate body weight, e.g., 30 to 150 kg, preferably 40 to 100 kg. The dosage, particles, and route of administration may be such that the dose of progeny nuclides generated in vivo is less than 300 kBq / kg, e.g., less than 200 kBq / kg, preferably less than 150 kBq / kg, e.g., less than 100 kBq / kg.

[0140] A diagnostically effective amount of the particles or compositions of the present invention can be administered in a single dose or in divided doses. The particles or compositions of the present invention can be administered once a day, twice or more, every two days, every three days, twice a week, or once a week, or as deemed appropriate by a medical professional and coordinated with the imaging procedure. In certain embodiments, the particles or compositions of the present invention are administered once a day, preferably immediately before the imaging procedure. In other embodiments, the dosage and frequency of treatment with the particles or compositions of the present invention will be determined by a medical professional based on factors including, but not limited to, the stage of the disease, the severity of symptoms, the route of administration, the subject's age, weight, general health, sex, and / or diet, and / or the subject's response to treatment.

[0141] The particles or compositions according to the invention should be administered by a medical professional. In some embodiments, the particles or compositions according to the invention are administered at specific times of day.

[0142] The particles or compositions for use as imaging agents and / or in diagnostic methods according to the present invention can be administered locally or systemically.The particles or compositions according to the present invention can be administered by any route of administration, including, but not limited to, pulmonary, oral, intraperitoneal, intravenous, intramuscular, intratumoral, sublingual, subcutaneous, intrahepatic, buccal, rectal, intravaginal, occipital, intranasal, transdermal, and intradermal.In some embodiments, the particles or compositions are administered intravenously.In these embodiments, water is a particularly useful excipient.Saline and aqueous solutions of dextrose and glycerol can also be employed as liquid excipients, particularly for injections.

[0143] The composition of the present invention can be presented in a unit dosage form as a single dose, where all active and inactive ingredients are combined in a suitable system and do not need to be mixed before administration. Alternatively, the composition can be presented as a kit as disclosed above, and can include instructions for storing, preparing, administering and / or using the composition.

[0144] In certain embodiments, the particles or compositions of the present invention are administered alone. In other embodiments, the particles or compositions of the present invention are administered in combination with one or more other imaging agents, for example, for use in imaging modalities other than radiopharmacology. When using separate formulations, the particles or compositions of the present invention can be administered simultaneously with, intermittently, at staggered times, before, after, or a combination thereof with the administration of another imaging agent.

[0145] Embodiments and features described in the context of certain aspects, such as aspects directed to particles or compositions, also apply to other aspects of the invention, such as their use as imaging agents or in diagnostic methods.

[0146] In a further aspect, the present invention provides a method of diagnosis, comprising administering an effective amount of a particle or composition of the present invention to a subject in need thereof.

[0147] In a further aspect, the present invention provides a method for diagnosing a proliferative disease, the method comprising administering an effective amount of a particle or composition of the present invention to a subject in need thereof.

[0148] In a further aspect, the present invention provides a method for diagnosing a chronic inflammatory disease, the method comprising administering an effective amount of a particle or composition of the present invention to a subject in need thereof.

[0149] In a further aspect, the present invention provides the use of a particle or composition of the invention as an imaging agent.

[0150] In a further aspect, the present invention provides the use of a particle or composition of the invention for the diagnosis of a proliferative disease.

[0151] In a further aspect, the present invention provides the use of a particle or composition of the invention for the diagnosis of a chronic inflammatory disease.

[0152] The present invention is not limited to the illustrated embodiments and examples. While various embodiments of the present disclosure have been described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous modifications and variations, as well as variations and substitutions to the embodiments described herein, will be apparent to those skilled in the art without departing from the present disclosure. It will be understood that various alternatives to the embodiments described herein may be employed in implementing the present disclosure.

[0153] It is to be understood that all embodiments of the present disclosure may be combined in any manner with any one or more of the other embodiments described herein.

[0154] It is understood that each component, compound, particle, or parameter disclosed herein is intended to be disclosed for use alone or in combination with one or more of the other components, compounds, or parameters disclosed herein. Furthermore, it is understood that each amount / value or amount / value range of each component, compound, or parameter disclosed herein is intended to be disclosed in combination with each amount / value or amount / value range disclosed for any other component, and any combination of amount / values ​​or amount / value ranges for two or more components, compounds, or parameters disclosed herein is therefore intended to be disclosed in combination with each other for purposes of this specification. Any and all features described herein, and combinations of such features, are included within the scope of the present invention, provided that the features are not mutually inconsistent.

[0155] It should be understood that each lower limit of each range disclosed herein is interpreted as a disclosure in combination with each upper limit of each range disclosed herein for the same component, compound, or parameter. Thus, a disclosure of two ranges is interpreted as a disclosure of four ranges derived by combining each lower limit with each upper limit of each range. A disclosure of three ranges is interpreted as a disclosure of nine ranges derived by combining each lower limit with each upper limit of each range. Furthermore, a specific amount / value of a component, compound, or parameter disclosed in the specification or examples is interpreted as a disclosure of either the lower or upper limit of a range, and therefore may be combined with other lower or upper limits, or ranges or specific amounts / values, of the same component, compound, or parameter disclosed elsewhere in this application to form a range for that component, compound, or parameter. [Example]

[0156] Example 1: Conjugation of anti-CD37 IgG to UIO-66-(COOH) UIO-66-(COOH)2 MOF was prepared by a method based on that of Zhiijie Chen et al., CrystEngComm 2019, 14, 2409-2415, except that the oxychloride salt was used as the precursor for the MOF instead of the oxynitrite salt. UIO-66-(COOH)2 antibody conjugation was evaluated by analyzing UIO-66-(COOH)2 antibody-conjugated particles using the bicinchoninic acid assay (BCA). The BCA protein assay measures Cu by protein in alkaline medium. 2+ Cu 1+ The well-known reduction of copper cations (Cu) to 1+ The first step is the chelation of copper with proteins in an alkaline environment, forming a pale blue complex. In this reaction, known as the biuret reaction, peptides containing three or more amino acid residues form a colored chelate complex with copper ions in an alkaline environment containing sodium potassium tartrate.

[0157] In the second step of the color reaction, BCA reacts with the reduced cation (cuprous ion) formed in the first step. A deep purple reaction product results from the chelation of two molecules of BCA with one cuprous ion.

[0158] procedure: Five milligrams of UIO-66-(COOH)2 was dissolved in 0.05 M 2-morpholinoethanesulfonic acid (MES) buffer, pH 6.3, and treated with 1.2 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and 1.2 mg of sodium N-hydroxysulfosuccinimide (sulfo-NHS) for 15 minutes. The particles were then washed twice with 0.05 M MES buffer, pH 6.3. The particles were then resuspended in 0.05 M MES buffer, pH 6.3, containing 100 μg of anti-CD37 IgG. The reaction mixture was incubated for 3 hours with continuous rocking. The MOF-antibody particles were washed with 0.05 M MES buffer, pH 6.3, and resuspended in 100 mM Tris buffer. The particles were then washed and stored in 0.05 M MES buffer, pH 6.3.

[0159] Antibody (IgG)-conjugated UIO-66-(COOH)2 and albumin standards were evaluated by the BCA assay shown in Figure 12. The albumin trend line equation was used to calculate the protein concentration of UIO-66-(COOH)2-IgG particles per mL: absorbance-blank: 0.096, equivalent to 77 μg / mL (77% of the antibody input amount).

[0160] Example 2: Structural stability and barium retention capacity of MOFs in human serum In this experiment, barium(II) was used as the cold isotope to mimic 133 / 131Ba.

[0161] procedure: 200 mg of UIO-66-(COOH)2 was washed once with 0.05 M MES buffer (pH 6.3) and suspended in 40 mL of aqueous barium(II) acetate (14.7 μg Ba / mL). The suspension was stirred at room temperature for 60 min. The MOF was recovered, washed once with 5 mL of 0.05 mol / L MES buffer (pH 6.3), and then suspended in human serum. The MOF / serum suspension was stirred at room temperature for 11 days. Samples were taken after 15 min and after 1, 2, 4, and 7 days. Elemental analysis was performed using MP-AES after digestion of the serum sample with a 1:1 volume mixture of HNO3 (65%) aq. and H2O2 (33%) aq. at 70 °C for 1 h.

[0162] Elemental analysis showed that the MOF adsorbed 97.2% of the Ba2+ in solution, with a Ba2+ concentration of 2.87 μg / mg (0.287% wt.) in the MOF. Analysis of serum samples taken after 15 min and 1, 2, 4, and 7 days indicated a total Ba2+ leakage into the serum of 6.6%, 8.4%, 9.4%, 8.3%, and 5.5%, respectively. This indicates that after the initial leakage, the MOF contained all of the Ba2+.

[0163] The MOF was isolated from the serum after 11 days and analyzed by powder X-ray diffraction and energy dispersive X-ray spectroscopy. The powder X-ray diffraction patterns of UIO-66-(COOH)2 as received and after the 11-day stability test clearly show that the crystalline structure of the MOF remains intact. EDS indicates that the Ba / Zr mass ratio in the MOF is 1.10%, which is comparable to the theoretical mass fraction of Zr in the MOF (25.1% from the formula Zr6O4(OH)4(COO)12(C8H4O4)6, which is 1.14%, and is in close agreement with the value measured by MP-AES (0.287% wt.), within experimental error.

[0164] [Table 2]

[0165] Therefore, this experiment demonstrates that the MOF particles themselves are stable in human serum for at least 11 days, and that the chelation of barium cations in the MOF particles is stable for at least 11 days. This experiment also demonstrates the ability of MOFs to adsorb significant amounts of Ca, K, and Na without leaking Ba.

[0166] Example 3: Structural stability and barium retention capacity of MOFs in human serum This example confirms the results of Example 2 using a different Ba2+ source and two different concentrations.

[0167] procedure: Two separate portions of 120 mg of UIO-66-(COOH)2 were washed three times with 5 mL of 0.05 mol / L MES buffer (pH 6.3) and then suspended in two separate 5 mL aqueous solutions of barium(II) nitrate (1.165 mg / mL Ba and 0.109 mg / mL Ba, respectively). The suspensions were stirred at room temperature for 90 min. The MOFs were recovered, washed once with 5 mL of 0.05 mol / L MES buffer (pH 6.3), and then suspended in human serum. Samples were taken after 24 and 48 h. The MOF / serum suspension was continued stirring at room temperature for 2 days. Samples were taken after 24 and 48 h. Elemental analysis was performed using MP-AES after digestion of the serum samples with a 1:1 volume mixture of HNO3 (65%) aq. and H2O2 (33%) aq. at 70 °C for 1 h.

[0168] From a 1.165 mg / mL Ba solution: Elemental analysis showed that the MOF adsorbed 98.8% of the Ba2+ in solution, resulting in a Ba2+ concentration of 48.0 μg / mg (4.8% wt.) in the MOF. Analysis of serum samples taken after 24 and 48 h showed a total Ba2+ leakage into the serum of 8.8% and 9.2%, respectively. This indicates that there was almost negligible Ba2+ leakage between 24 and 48 h. EDS showed that the Ba / Zr mass ratio in the MOF was 19.4%, which is comparable to the theoretical mass fraction of Zr in the MOF (25.1% from the formula Zr6O4(OH)4(COO)12(C8H4O4)6), and is in close agreement, within experimental error, with the value measured by MP-AES (4.8% wt.).

[0169] From a 0.109 mg / mL Ba solution: Elemental analysis showed that the MOF adsorbed 92.0% of the Ba2+ in solution, resulting in a Ba2+ concentration of 4.19 μg / mg (0.42% wt.) in the MOF. Analysis of serum samples taken after 24 and 48 hours showed a total Ba2+ leakage into the serum of 6.4% and 6.0%, respectively. This indicates that there was no Ba2+ leakage between 24 and 48 hours. EDS showed that the Ba / Zr mass ratio in the MOF was 1.43%, compared to the theoretical mass fraction of Zr in the MOF (25.1% from the formula Zr6O4(OH)4(COO)12(C8H4O4)6 of 1.67%, which is in close agreement, within experimental error, with the value measured by MP-AES (0.42% wt.).

[0170] [Table 3]

[0171] Example 4: MOF-IgG cell interactions This example demonstrates that anti-CD37 conjugated MOF (NP1) binds to CD37-positive cells (Daudi cells). The Daudi cell line consists of B lymphoblasts isolated from the peripheral blood of a patient with Burkitt's lymphoma, demonstrating that anti-CD37 conjugated MOF can identify blood-borne cancer cells.

[0172] procedure: Sixty-six thousand Daudi cells were transferred to flow tubes containing phosphate-buffered saline (PBS), an isotype control, a UIO-66-(COOH)2 anti-CD37 stability test sample (incubated at 20°C for 6 months), or a freshly conjugated sample of UIO-66-(COOH)2 anti-CD37. The samples were incubated for 30 minutes with continuous mixing, after which 400 μL of 10% fetal bovine serum (FBS) in PBS was added and centrifuged at 350×g for 8 minutes. The supernatant was discarded, and then 100 μL of anti-CD37-PE (10 μL of anti-CD37-PE mixed with 90 μL of PBS) was added to the PBS samples, or 100 μL of anti-mouse-PE (10 μL of anti-mouse-PE mixed with 90 μL of PBS) was added to the isotype control and UIO-66-(COOH)2a CD37 samples. The samples were incubated for 30 minutes with continuous mixing, after which 400 μL of 10% FBS in PBS was added and centrifuged at 350 g for 8 minutes, the supernatant was discarded, and then 400 μL of 10% FBS in PBS was added and flow cytometry analysis was performed.

[0173] The stability control sample used in this experiment was prepared by storing UIO-66-(COOH)2 anti-CD37 at 20°C for 6 months.

[0174] FIG. 13 provides results showing that anti-CD37 conjugated MOF (NP1) binds to CD37-positive cells and is stable at room temperature for at least 6 months.

[0175] Example 5: Cellular binding of MOF-anti-EpCAM and MOF-anti-HER2 to colorectal cell lines This example demonstrates that UIO-66-(COOH)2 conjugated to either anti-EpCAM or anti-HER binds to colon cancer cells (HTC116 and HT29) expressing both antigens. HTC116 cells were derived from the colon of an adult male patient with colon cancer. HT29 cell line was derived from the primary tumor of a female patient with colon adenocarcinoma. Therefore, we demonstrate that UIO-66-(COOH)2 conjugated to both anti-EpCAM and anti-HER antibodies (IgG) can identify cancer cells derived from the colon.

[0176] procedure: Cells were seeded at 50,000 cells per well in a 96-well plate and cultured overnight in Roswell Park Memorial Institute (RPMI) complete cell culture medium supplemented with 10% fetal bovine serum (FBS). The next day, the medium was discarded from each well, and 2 μg of anti-EpCAM, 2 μg of isotype control, or 15 μL of UIO-66-(COOH)2 (NP1) diluted in prewarmed cell culture medium was added to a total volume of 200 μL per well. Samples were incubated at 37°C for 30 minutes, after which the medium was discarded and 200 μL of phosphate-buffered saline (PBS) was gently added twice. 100 μL of PBS and 100 μL of anti-human IgG-HRP solution (2.5 μL anti-human IgG-HRP solution / mL) were added per sample and incubated at room temperature for 30 minutes. After secondary staining, cells were gently washed twice with PBS, and then 100 μL of TMB (3,3',5,5'-tetramethylbenzidine) HRP (horseradish peroxidase) substrate solution was added to each well and incubated for 15 minutes. 100 μL of stop solution was added per well to stop the reaction before measuring the absorbance of each well at 450 nm. The absorbance is displayed on the graph as "HRP signal."

[0177] FIG. 14 shows that anti-EpCAM and anti-HER2 UIO-66-(COOH) 2 bind colon cancer cells (HTC116 and HT29).

[0178] Example 6: MOF-anti-HER2 breast cancer cell interactions This experiment demonstrates that anti-HER2 conjugate UIO-66-(COOH)2 binds HER2-positive cancer cells (JIMT1 cells). JIMT1 cells are epithelial cells derived from a female patient with breast ductal adenocarcinoma. Therefore, the interaction with JIMT1 cells demonstrates how anti-HER2 conjugate UIO-66-(COOH)2 can identify cancer cells derived from the breast.

[0179] Procedure: The same procedure as for colon cancer cell interaction was used for JIMT1 cell interaction, see Example 5 (Figure 14).

[0180] FIG. 15 provides results showing that anti-HER2 conjugate UIO-66-(COOH) 2 binds to breast cancer JIMT1 cells.

[0181] Example 7: In fetal bovine serum 68 Ga 3+ Adsorption and retention of MOFs Procedure: Two suspensions of UiO-66-(COOH)2 conjugated to anti-EpCAM antibody and polyethylene glycol (PEG) were prepared at MOF concentrations of 175 mg / L (A) and 250 mg / L (B) in 20 mM histidine chloride buffer (pH 7). 68 GaCl3 solution was added to the desired radioactivity concentration (RAC): 50 MBq / mL in A and 30 MBq / mL in B. After 10 min, each dose was added to fetal bovine serum (FBS) at the concentration of diagnostic injection solution, a volume of 25 μL each in 400 μL FBS. After 15 min, serum samples were filtered through 100 kDa molecular weight cutoff filters in a centrifuge (14,000 g, 10 min) using a Hidex gamma counter device to separate the MOF binding activity in the filter from the dissociation activity in the filtrate. Sample A showed 87% retention, and sample B showed 89% retention. Baseline correction was applied (using a control without MOF in parallel).

[0182] Example 8: In healthy mice 68 Biodistribution of Ga-loaded UIO-66-(COOH)2 Procedure: A 0.6 MBq dose of Sample B from Example 7 was suspended in 5 wt% glucose solution for injection into healthy mice, which were analyzed by PET / CT to assess biodistribution at consecutive time points.

[0183] Figure 17 shows sections of a mouse PET / CT scan overlay after administration of a 0.6 MBq dose of 68Ga-labeled NPs. Images were acquired 10-30 minutes after injection. Results: 68 This indicates that activity from Ga-loaded UIO-66-(COOH)2 was primarily found in the liver and bladder, with some accumulation in the spleen. 68 Since GaCl3 will be found throughout the body, in the blood, and in the bladder, 68 Ga]GaCl3 solution or 68 This biodistribution is significantly different from that of Ga-labeled molecules (Steinberg, JD, Raju, A., Chandrasekharan, PET al. Negative contrast Cerenkov luminescence imaging of blood vessels in a tumor mouse model using [68Ga] gallium chloride. EJNMMI Res 4, 15 (2014). https: / / doi.org / 10.1186 / 2191-219X-4-15).

[0184] Example 9. Designed Experiment: Biodistribution of UIO-66-(COOH)2 (NP) conjugated to anti-HER2 antibody, anti-EpCAM antibody, and polyethylene glycol (PEG) to investigate tumor targeting of NPs with and without antibodies procedure: The biodistribution of UIO-66-(COOH)2 targeting EpCAM or HER2, along with their tumor localization ability, will be investigated using tumor models representing HER2+ breast cancer and EpCAM colon cancer. To examine the specificity of the nanoparticles (NPs), antibody-conjugated and non-antibody-conjugated NPs will be used in addition to radioactivity. Mice will be sacrificed between days 0 and 30 after treatment to examine the drug's biodistribution over time and whether its biodistribution is specific to the tumor. For the two EpCAM-targeting drugs, this will be examined in two or more models (e.g., HCT116 and HT29) using tumors growing in the liver and the peritoneal cavity. For tumors growing in the peritoneal cavity, the agent will be injected either intravenously (i.v.) or intraperitoneally (i.p.) to determine which injection form has the best biodistribution for tumors growing in the peritoneal cavity. Two HER2-targeted agents will be examined in at least two models, such as SKBR3 (cell line) and BBRC160 (PDX), which produce breast, liver, and peritoneal tumors.

[0185] Example 10. Viability studies of PEG-conjugated UiO-66-(COOH)2 (NP) show no toxicity in vitro. Exposure of HT29 and HCT116 to increasing doses of NPs for 2 days before analyzing cell viability shows that NPs do not induce cell death under these conditions.

[0186] procedure: HT29 or HCT116 cells were exposed to 0.001–500 μg / well of UiO-66-(COOH)2 (NP) and cultured for 24 and 48 h at 37°C and 5% CO2 in a humidified incubator before discarding the supernatant and adding 100 μL of fresh cell culture medium (10% fetal bovine serum (FBS), Roswell Park Memorial Institute (RPMI)) and 20 μL of CellTiter 96® AQueous One Solution Reagent (Promega) containing the tetrazolium compound [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inert salt, MTS] and electron coupling reagent (phenazine ethosulfate; PES). Each plate was incubated in a humidified incubator at 37°C and 5% CO2 for 1.5 hours before measuring absorbance at 490 nm with a plate reader.

[0187] Figures 16A and B show the in vitro cell viability of HT29 or HCT116 cells after 24 and 48 hours of exposure to UiO-66-(COOH)2, respectively. The absorbance remained unchanged under all conditions, indicating that the cell content per well did not change over the 48-hour period.

Claims

1. A particle, a repeating three-dimensional network of inorganic and organic monomers that forms pores; and at least one free functional group extending into the pore, said free functional group being selected from the group including carboxylic acid, carboxylate, hydroxyl, sulfonic acid, sulfonate, sulfhydryl, primary amine, secondary amine, and combinations thereof; MOFs comprising: Optionally, at least one targeting moiety linked to the particle on the outer surface of the particle; and at least one short-lived radionuclide; Including, wherein said at least one radionuclide is located in at least one of said pores.

2. 2. The particle of claim 1, wherein the MOF is a Zr(IV), Hf(IV), Ce(IV), Fe(III), Al(III), Ti(IV), or Cr(III)-based MOF with a carboxylate organic monomer, or a Zn(II) imidazolate-based MOF.

3. The MOF is UiO-66-COOH, MOF-808, or UIO-66(COOH). 2 3. The particle according to claim 1 or 2, wherein

4. 4. The particle according to claim 1, wherein the radionuclide is a gamma-ray emitting nuclide or a positron emitting nuclide.

5. 5. The particle of any one of claims 1 to 4, wherein the radionuclide has a half-life of between 0.5 hours and 60 days.

6. 6. The particle of any one of claims 1 to 5, wherein the at least one radionuclide is selected from the group comprising Ga-68, Ti-45, Tc-99m, Ba-133m, F-18, In-111, Ga-67, Zr-89, Ba-131, Yb-169 and Sc-43.

7. The particle according to any one of claims 1 to 6, wherein the particle is a nanoparticle.

8. A particle according to any one of claims 1 to 7, wherein said at least one target site is present.

9. The particle of any one of claims 1 to 8, wherein the at least one targeting moiety is present and is an antibody.

10. In the first container: A particle, a repeating three-dimensional network of inorganic and organic monomers that forms pores; and at least one free functional group extending into the pore, said functional group being selected from the group including carboxylic acid, carboxylate, hydroxyl, sulfonic acid, sulfonate, sulfhydryl, primary amine, secondary amine, and combinations thereof; MOFs comprising: Optionally, at least one targeting moiety attached to said particle on the outer surface of said particle; and In the second container, short-lived radionuclides Kit including:

11. An imaging agent composition comprising at least one particle according to any one of claims 1 to 9 together with at least one pharmaceutically acceptable carrier, diluent and / or excipient.

12. A particle according to any one of claims 1 to 9 or a composition according to claim 11 for use as an imaging agent in vivo.

13. A particle according to any one of claims 1 to 9 or a composition according to claim 11 for use in a method for the diagnosis of a proliferative disease.

14. The particle according to any one of claims 1 to 9 or the composition according to claim 11 for the use according to claim 13, wherein the proliferative disease is cancer.

15. The particle of any one of claims 1 to 9 or the composition of claim 11 for use according to claim 14, wherein the cancer is carcinoma, sarcoma, myeloma, leukemia, lymphoma or mixed cancer.

16. The particle according to any one of claims 1 to 9 or the composition according to claim 11 for the use according to claim 13, wherein the proliferative disorder is a hyperplastic disorder or a neoplastic disorder.

17. A particle according to any one of claims 1 to 9 or a composition according to claim 11 for use in a method for the diagnosis of a chronic inflammatory disease.

18. 12. The particle of any one of claims 1 to 9 or the composition of claim 11 for use in a method for the diagnosis of a subject followed by a subsequent treatment step with particles comprising the same MOF as used in the diagnosis, the MOF carrying a therapeutic radionuclide.

19. A particle according to any one of claims 1 to 9 or a composition according to claim 11 for use in a method for the diagnosis of liver cancer, wherein the particle does not comprise a targeting moiety.

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